@article{FringsGoebelerSchillingetal.2021, author = {Frings, Verena Gerlinde and Goebeler, Matthias and Schilling, Bastian and Kneitz, Hermann}, title = {Aberrant cytoplasmic connexin43 expression as a helpful marker in vascular neoplasms}, series = {Journal of Cutaneous Pathology}, volume = {48}, journal = {Journal of Cutaneous Pathology}, number = {11}, doi = {10.1111/cup.14066}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258412}, pages = {1335-1341}, year = {2021}, abstract = {Background Gap junctions consisting of connexins (Cx) are fundamental in controlling cell proliferation, differentiation, and cell death. Cx43 is the most broadly expressed Cx in humans and is attributed an important role in skin tumor development. Its role in cutaneous vascular neoplasms is yet unknown. Methods Fifteen cases each of cutaneous angiosarcoma (cAS), Kaposi sarcoma (KS), and cherry hemangioma (CH) were assessed by immunohistochemistry for expression of Cx43. Expression pattern, intensity, and percentage of positively stained cells were analyzed. Solid basal cell carcinomas served as positive and healthy skin as negative controls. Results Most cases of cAS presented with a strong Cx43 staining of almost all tumor cells, whereas endothelia of KS showed medium expression and CH showed mostly weak expression. In comparison with KS or cAS, the staining intensity of CH was significantly lower (P ≤ 0.001). All tissue sections of both cAS and KS were characterized by a mostly diffuse, cytoplasmic staining pattern of the vascular endothelia. None of those showed nuclear staining. Conclusion The high-to-intermediate expression of Cx43 observed in all cases of cAS and KS suggests that this Cx may play a role in the development of malignant vascular neoplasms and serve as a helpful diagnostic marker.}, language = {en} } @article{GlutschKneitzGesierichetal.2021, author = {Glutsch, Valerie and Kneitz, Hermann and Gesierich, Anja and Goebeler, Matthias and Haferkamp, Sebastian and Becker, J{\"u}rgen C. and Ugurel, Selma and Schilling, Bastian}, title = {Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma}, series = {Cancer Immunology, Immunotherapy}, volume = {70}, journal = {Cancer Immunology, Immunotherapy}, number = {7}, issn = {14320851}, doi = {10.1007/s00262-020-02832-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265635}, pages = {2087-2093}, year = {2021}, abstract = {Background Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cutaneous malignancy with poor prognosis. In Europe, approved systemic therapies are limited to the PD-L1 inhibitor avelumab. For avelumab-refractory patients, efficient and safe treatment options are lacking. Methods At three different sites in Germany, clinical and molecular data of patients with metastatic MCC being refractory to the PD-L1 inhibitor avelumab and who were later on treated with combined IPI/NIVO were retrospectively collected and evaluated. Results Five patients treated at three different academic sites in Germany were enrolled. Three out of five patients investigated for this report responded to combined IPI/NIVO according to RECIST 1.1. Combined immunotherapy was well tolerated without any grade II or III immune-related adverse events. Two out of three responders to IPI/NIVO received platinum-based chemotherapy in between avelumab and combined immunotherapy. Conclusion In this small retrospective study, we observed a high response rate and durable responses to subsequent combined immunotherapy with IPI/NIVO in avelumab-refractory metastatic MCC patients. In conclusion, our data suggest a promising activity of second- or third-line PD-1- plus CTLA-4-blockade in patients with anti-PD-L1-refractory MCC.}, language = {en} } @article{WendlingerWohlfarthKreftetal.2022, author = {Wendlinger, Simone and Wohlfarth, Jonas and Kreft, Sophia and Siedel, Claudia and Kilian, Teresa and Dischinger, Ulrich and Heppt, Markus V. and Wistuba-Hamprecht, Kilian and Meier, Friedegund and Goebeler, Matthias and Schadendorf, Dirk and Gesierich, Anja and Kosnopfel, Corinna and Schilling, Bastian}, title = {Blood eosinophils are associated with efficacy of targeted therapy in patients with advanced melanoma}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {9}, issn = {2072-6694}, doi = {10.3390/cancers14092294}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275137}, year = {2022}, abstract = {Background: Eosinophils appear to contribute to the efficacy of immunotherapy and their frequency was suggested as a predictive biomarker. Whether this observation could be transferred to patients treated with targeted therapy remains unknown. Methods: Blood and serum samples of healthy controls and 216 patients with advanced melanoma were prospectively and retrospectively collected. Freshly isolated eosinophils were phenotypically characterized by flow cytometry and co-cultured in vitro with melanoma cells to assess cytotoxicity. Soluble serum markers and peripheral blood counts were used for correlative studies. Results: Eosinophil-mediated cytotoxicity towards melanoma cells, as well as phenotypic characteristics, were similar when comparing healthy donors and patients. However, high relative pre-treatment eosinophil counts were significantly associated with response to MAPKi (p = 0.013). Eosinophil-mediated cytotoxicity towards melanoma cells is dose-dependent and requires proximity of eosinophils and their target in vitro. Treatment with targeted therapy in the presence of eosinophils results in an additive tumoricidal effect. Additionally, melanoma cells affected eosinophil phenotype upon co-culture. Conclusion: High pre-treatment eosinophil counts in advanced melanoma patients were associated with a significantly improved response to MAPKi. Functionally, eosinophils show potent cytotoxicity towards melanoma cells, which can be reinforced by MAPKi. Further studies are needed to unravel the molecular mechanisms of our observations.}, language = {en} } @article{SchoenBerkingBiedermannetal.2020, author = {Sch{\"o}n, Michael P. and Berking, Carola and Biedermann, Tilo and Buhl, Timo and Erpenbeck, Luise and Eyerich, Kilian and Eyerich, Stefanie and Ghoreschi, Kamran and Goebeler, Matthias and Ludwig, Ralf J. and Sch{\"a}kel, Knut and Schilling, Bastian and Schlapbach, Christoph and Stary, Georg and von Stebut, Esther and Steinbrink, Kerstin}, title = {COVID-19 and immunological regulations - from basic and translational aspects to clinical implications}, series = {JDDG: Journal der Deutschen Dermatologischen Gesellschaft}, volume = {18}, journal = {JDDG: Journal der Deutschen Dermatologischen Gesellschaft}, number = {8}, doi = {10.1111/ddg.14169}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218205}, pages = {795 -- 807}, year = {2020}, abstract = {The COVID-19 pandemic caused by SARS-CoV-2 has far-reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS-CoV-2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS-CoV-2/COVID-19 with mediators of the acute phase of inflammation (TNF, IL-1, IL-6), type 1 and type 17 immune responses (IL-12, IL-23, IL-17, IL-36), type 2 immune reactions (IL-4, IL-13, IL-5, IL-31, IgE), B-cell immunity, checkpoint regulators (PD-1, PD-L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non-specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte-mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS-CoV-2/COVID-19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID-19 pandemic; some even appear to alleviate COVID-19.}, language = {en} } @article{LoddeForschnerHasseletal.2021, author = {Lodde, Georg and Forschner, Andrea and Hassel, Jessica and Wulfken, Lena M. and Meier, Friedegund and Mohr, Peter and K{\"a}hler, Katharina and Schilling, Bastian and Loquai, Carmen and Berking, Carola and H{\"u}ning, Svea and Schatton, Kerstin and Gebhardt, Christoffer and Eckardt, Julia and Gutzmer, Ralf and Reinhardt, Lydia and Glutsch, Valerie and Nikfarjam, Ulrike and Erdmann, Michael and Stang, Andreas and Kowall, Bernd and Roesch, Alexander and Ugurel, Selma and Zimmer, Lisa and Schadendorf, Dirk and Livingstone, Elisabeth}, title = {Factors influencing the adjuvant therapy decision: results of a real-world multicenter data analysis of 904 melanoma patients}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {10}, issn = {2072-6694}, doi = {10.3390/cancers13102319}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239583}, year = {2021}, abstract = {Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9\% (95\% CI 74-80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26\% lower in patients >65 years (RR 0.74, 95\% CI 68-80). The most common reasons against adjuvant treatment given by patients were age (29.4\%, 95\% CI 24-38), and fear of adverse events (21.1\%, 95\% CI 16-28) and impaired quality of life (11.9\%, 95\% CI 7-16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9\% (95\% CI 47-59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.}, language = {en} } @article{SchummerSchilling2022, author = {Schummer, Patrick and Schilling, Bastian}, title = {How representative are data from global trials on programmed death-1 blockade in melanoma?}, series = {The British Journal of Dermatology}, volume = {187}, journal = {The British Journal of Dermatology}, number = {3}, doi = {10.1111/bjd.21621}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318406}, pages = {283 -- 284}, year = {2022}, language = {en} } @article{GlutschAmaralGarbeetal.2020, author = {Glutsch, Valerie and Amaral, Teresa and Garbe, Claus and Thoms, Kai-Martin and Mohr, Peter and Hauschild, Axel and Schilling, Bastian}, title = {Indirect Comparison of Combined BRAF and MEK Inhibition in Melanoma Patients with Elevated Baseline Lactate Dehydrogenase}, series = {Acta Dermato-Venereologica}, volume = {100}, journal = {Acta Dermato-Venereologica}, doi = {10.2340/00015555-3526}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230190}, year = {2020}, abstract = {The approval of BRAF and MEK inhibitors has signifi-cantly improved treatment outcomes for patients with BRAF-mutated metastatic melanoma. The 3 first-line targeted therapy trials have provided similar results, and thus the identification of predictive biomarkers may generate a more precise basis for clinical deci-sion-making. Elevated baseline lactate dehydrogenase (LDH) has already been determined as a strong prog-nostic factor. Therefore, this indirect analysis compa-red subgroups with elevated baseline LDH across the pivotal targeted therapy trials co-BRIM, COMBI-v and COLUMBUS part 1. The Bucher method was used to compare progression-free survival, objective response rate and overall survival indirectly. The results show a non-significant risk reduction for progression in the subgroup with elevated baseline LDH receiving vemu-rafenib plus cobimetinib compared with dabrafenib plus trametinib and encorafenib plus binimetinib. Al-though an indirect comparison, these data might pro-vide some guidance for treatment recommendations in melanoma patients with elevated LDH.}, language = {en} } @article{GlutschSchummerKneitzetal.2022, author = {Glutsch, Valerie and Schummer, Patrick and Kneitz, Hermann and Gesierich, Anja and Goebeler, Matthias and Klein, Detlef and Posch, Christian and Gebhardt, Christoffer and Haferkamp, Sebastian and Zimmer, Lisa and Becker, J{\"u}rgen C and Leiter, Ulrike and Weichenthal, Michael and Schadendorf, Dirk and Ugurel, Selma and Schilling, Bastian}, title = {Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG}, series = {Journal for ImmunoTherapy of Cancer}, volume = {10}, journal = {Journal for ImmunoTherapy of Cancer}, number = {11}, issn = {2051-1426}, doi = {10.1136/jitc-2022-005930}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304613}, year = {2022}, abstract = {Merkel cell carcinoma is a rare, highly aggressive skin cancer with neuroendocrine differentiation. Immune checkpoint inhibition has significantly improved treatment outcomes in metastatic disease with response rates to programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibition of up to 62\%. However, primary and secondary resistance to PD-1/PD-L1 inhibition remains a so far unsolved clinical challenge since effective and safe treatment options for these patients are lacking.Fourteen patients with advanced (non-resectable stage III or stage IV, Union international contre le cancer 2017) Merkel cell carcinoma with primary resistance to the PD-L1 inhibitor avelumab receiving subsequent therapy (second or later line) with ipilimumab plus nivolumab (IPI/NIVO) were identified in the prospective multicenter skin cancer registry ADOREG. Five of these 14 patients were reported previously and were included in this analysis with additional follow-up. Overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events were analyzed.All 14 patients received avelumab as first-line treatment. Thereof, 12 patients had shown primary resistance with progressive disease in the first tumor assessment, while two patients had initially experienced a short-lived stabilization (stable disease). Six patients had at least one systemic treatment in between avelumab and IPI/NIVO. In total, 7 patients responded to IPI/NIVO (overall response rate 50\%), and response was ongoing in 4 responders at last follow-up. After a median follow-up of 18.85 months, median PFS was 5.07 months (95\% CI 2.43—not available (NA)), and median OS was not reached. PFS rates at 12 months and 24 months were 42.9\% and 26.8 \%, respectively. The OS rate at 36 months was 64.3\%. Only 3 (21\%) patients did not receive all 4 cycles of IPI/NIVO due to immune-related adverse events.In this multicenter evaluation, we observed high response rates, a durable benefit and promising OS rates after treatment with later-line combined IPI/NIVO. In conclusion, our patient cohort supports our prior findings with an encouraging activity of second-line or later-line IPI/NIVO in patients with anti-PD-L1-refractory Merkel cell carcinoma.}, language = {en} } @article{StepulaKoenigWangetal.2020, author = {Stepula, Elzbieta and K{\"o}nig, Matthias and Wang, Xin-Ping and Levermann, Janina and Schimming, Tobias and Kasimir-Bauer, Sabine and Schilling, Bastian and Schl{\"u}cker, Sebastian}, title = {Localization of PD-L1 on single cancer cells by iSERS microscopy with Au/Au core/satellite nanoparticles}, series = {Journal of Biophotonics}, volume = {13}, journal = {Journal of Biophotonics}, number = {3}, doi = {10.1002/jbio.201960034}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212655}, year = {2020}, abstract = {Programmed cell death-ligand 1 (PD-L1) is an important predictive biomarker. The detection of PD-L1 can be crucial for patients with advanced cancer where the use of immunotherapy is considered. Here, we demonstrate the use of immuno-SERS microscopy (iSERS) for localizing PD-L1 on single cancer SkBr-3 cells. A central advantage of iSERS is that the disturbing autofluorescence from cells and tissues can be efficiently minimized by red to near-infrared laser excitation. In this study we employed Au/Au core/satellite nanoparticles as SERS nanotags because of their remarkable signal brightness and colloidal stability upon red laser excitation. False-color iSERS images of the positive and negative controls clearly reveal the specific localization of PD-L1 with SERS nanotag-labeled antibodies.}, language = {en} } @article{SchummerSchillingGesierich2020, author = {Schummer, Patrick and Schilling, Bastian and Gesierich, Anja}, title = {Long‑Term Outcomes in BRAF‑Mutated Melanoma Treated with Combined Targeted Therapy or Immune Checkpoint Blockade: Are We Approaching a True Cure?}, series = {American Journal of Clinical Dermatology}, volume = {21}, journal = {American Journal of Clinical Dermatology}, issn = {1175-0561}, doi = {10.1007/s40257-020-00509-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234818}, pages = {493-504}, year = {2020}, abstract = {Approximately 50\% of all melanomas harbor an activating BRAF mutation. In patients suffering from an advanced melanoma with such a somatic alteration, combined targeted therapy with a BRAF and MEK inhibitor can be applied to significantly increase the survival probability. Nevertheless, resistance mechanisms, as well as negative predictive biomarkers (elevated lactate dehydrogenase levels, high number of metastatic organ disease sites, brain metastasis), remain a major problem in treating melanoma patients. Recently, a landmark overall survival (OS) rate of 34\% after 5 years of combined targeted therapy in treatment-na{\"i}ve patients was reported. On the other hand, patients harboring a BRAF mutation and receiving first-line immune checkpoint blockade with ipilimumab plus nivolumab showed a 5-year OS rate of 60\%. As indicated by these data, long-term survival can be reached in melanoma patients but it remains unclear if this is equivalent to reaching a true cure for metastatic melanoma. In this review, we summarize the recent results for combined targeted therapy and immunotherapy in advanced melanoma harboring an activating BRAF mutation and discuss the impact of baseline characteristics on long-term outcome.}, language = {en} }